The sulfated oligosaccharide agent known as PI-881,2 is a promising inhibitor of tumour growth and metastasis3,4,1 and has undergone clinical trials in cancer patients5,6. PI-88 is a mixture of highly sulfated, monophosphorylated mannose oligosaccharides ranging in size from di- to hexasaccharide7,8. PI-88 exerts antiangiogenic effects by inhibiting the interactions of angiogenic growth factors (principally FGF-1, FGF-2 and VEGF) and their receptors with heparan sulfate9,1. In addition, PI-88 is a potent inhibitor of the enzyme heparanase, a glycosidase that cleaves the heparan sulfate side chains of proteoglycans that are a major constituent of the extracellular matrix (ECM) and basement membranes surrounding tumour cells1,2. Heparanase has been strongly implicated in angiogenesis: it is able to liberate active heparan sulfate-bound angiogenic growth factors from the ECM and is involved in the degradation of the ECM and subsequent tissue remodeling associated with the sprouting of new blood vessels10. The degradation of the ECM by heparanase is also crucial in the spread of tumour cells (metastasis) by allowing them to pass into the blood stream and lodge in remote sites where they can form secondary tumours11,10.
In addition to its antiangiogenic effects, PI-88 inhibits the blood coagulation cascade by (i) inhibiting proteases in the intrinsic pathway, (ii) stimulating the release of tissue factor pathway inhibitor (TFPI), and (iii) activating the heparin cofactor II-mediated inhibition of thrombin. However, PI-88 does not interact with AT III and thus shows no anti-Xa or AT III-mediated anti-IIa activity12,13. In vivo studies in monkeys have shown that low doses of PI-88 stimulate release of all heparan sulfate bound TFPI from the vascular cell wall12. Apart from its effect on coagulation, TFPI is also an antiangiogenic agent14 and an inhibitor of metastasis15. PI-88 has also been shown to block vascular smooth muscle cell proliferation and intimal thickening16, to inhibit herpes simplex virus (HSV) infection of cells and the cell-to-cell spread of HSV-1 and HSV-217, to inhibit infectivity and improve survival in murine models of dengue and encephalitic flaviviruses,18 to inhibit proteinuria in passive Heymann nephritis19 and to display in vitro antimalarial activity against Plasmodium falciparum20.
Various other polysulfated oligo- and polysaccharides and their derivatives are well known to exhibit similar types of biological activities to PI-8821-26. These biological activities are attributed to the inhibition of various heparan sulfate (HS)-binding proteins. Recently, some sulfated oligosaccharide derivatives were disclosed with improved pharmacokinetic and/or ADME (absorption, distribution, metabolism, excretion) profiles27,28. The compounds comprised a single carbon skeleton and thus also provide synthesis and characterization advantages over mixtures such as PI-88.
The object of the present invention is the creation of HS-mimetics with even greater potency, improved pharmacokinetic properties and a reduced side effect profile.